Geometric-based and Physics-based Simulations of RNA Folding

描述（由申请人提供）：该提案的主要目的是促进我们对RNA稳定性，折叠和动力学的理解。由于RNA分子的生物学功能主要取决于其形状，我们相信实现这一目标将需要开发（a）表征RNA形状的几何形状和稳定性的新方法，（B）表征RNA折叠时出现的中间体的新技术，以及（c）描述RNA序列空间和结构空间之间的映射的新方法。该提案成功的关键在于其与NIH国家生物医学计算中心“基于物理的生物结构模拟”的合作集成，该中心位于斯坦福大学，由Russ Altman教授领导。斯坦福大学中心的几位Pis，包括Altman、Levitt和Pande教授在RNA动力学领域的专业知识，威尔斯他们开发的SimTK库中许多结构生物学计算方法的可用性，将证明对成功是无价的。特别是，我们将在以下具体目标上进行合作：（1）基于我们最初为研究蛋白质溶剂化而开发的成功方法，开发快速，准确和分析方法来测量RNA分子的几何性质。我们感兴趣的是，特别是在计算表面可及性，并在相关的几何措施，如羟基自由基足迹的实验数据。(2)开发一种新的计算RNA周围静电场的形式。我们建议使用广义泊松-玻尔兹曼-朗之万方程来描述RNA在水中产生的静电场，基于溶剂作为自由取向偶极子的组装的描述。(3)使用扭转和笛卡尔空间中的正交简正模来表征RNA动力学。我们特别感兴趣的是使用物理或弹性正常模式的组合来定义RNA分子的潜在构象之间的通路。(4)描述与RNA三级结构相容的序列空间。我们将应用我们为蛋白质序列设计开发的方法来测量RNA接受突变而不失去其结构的能力。(5)RNA结构的几何和物理性质的可视化。我们将扩展斯坦福大学开发的ToRNADo RNA可视化平台，使其成为理论和生物学之间的有效接口。

DESCRIPTION (provided by applicant): The main aim of this proposal is to advance our understanding of RNA stability, folding and dynamics. As the biological function of an RNA molecule mostly depends on its shape, we believe that achieving this aim will require the development of (a) new approaches to characterize the geometry and stability of RNA shapes, (b) new techniques to characterize intermediates that appear upon RNA folding, and (c) new methods to describe the map between RNA sequence space and structure space. The key to the success of this proposal lies in its collaborative integration within the NIH National Center for Biomedical Computing "Physics-based Simulation of Biological Structures", hosted at Stanford University, and lead by Prof. Russ Altman. The expertise of several Pis at the Stanford Center, including Profs Altman, Levitt and Pande, in the field of RNA dynamics as wells as the availability of many computational methods for structural biology in the SimTK library they have developed will prove invaluable for success. In particular, we will collaborate on the following specific aims: (1) Develop fast, accurate and analytic methods to measure geometric properties of RNA molecules, based on the successful methods we have originally developed for studying protein solvation. We are interested in particular in computing surface accessibility, and in correlating this geometric measure to experimental data such as hydroxyl radical footprinting. (2) Develop a new formalism for computing the electrostatic field around RNA. We propose to use a generalized Poisson-Boltzmann-Langevin equation to describe the electrostatic field generated by RNA in water, based on a description of the solvent as an assembly of freely orienting dipoles. (3) Use orthogonal normal modes in torsion and Cartesian space to characterize RNA dynamics. We are particularly interested in defining pathways between potential conformations of a RNA molecule using a combination of physical or elastic normal modes. (4) Describe the sequence space compatible with a RNA tertiary structure. We will apply the methods we have developed for protein sequence design to measure the ability of RNA to accept mutations without losing its structure. (5) Visualization of the geometric and physical properties of RNA structures. We will expand the ToRNADo RNA visualization platform developed at Stanford into an effective interface between theory and biology.